Altered transmission of HOX and apoptotic SNPs identify a potential common pathway for clubfoot.
Altered transmission of HOX and apoptotic SNPs identify a potential common pathway for clubfoot.
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DOI：
10.1002/ajmg.a.33130
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发表时间：
2009-12
影响因子：
2
通讯作者：
Hecht, Jacqueline T.
中科院分区：
文献类型：
--
作者：
Ester, Audrey R.;Weymouth, Katelyn S.;Burt, Amber;Wise, Carol A.;Scott, Allison;Gurnett, Christina A.;Dobbs, Matthew B.;Blanton, Susan H.;Hecht, Jacqueline T.
马蹄内翻足是一种常见的出生缺陷，每年影响全球135，000名新生儿。其特征是单足或双足马蹄足畸形和小腿肌肉发育不全。尽管有许多研究方法，但病因仍然知之甚少，尽管多因素病因学被普遍接受。我们认为HOXA和HOXD基因簇和胰岛素样生长因子结合蛋白3（IGFBP 3）作为候选基因，因为它们在肢体和肌肉形态发生中的重要作用。在由非西班牙裔白色和西班牙裔多重和单一家族组成的样品（发现样品）和非西班牙裔白色单一三人组的第二样品（验证样品）中，对来自HOXA和HOXD基因簇的20个SNP和IGFBP 3中的12个SNP进行基因分型。HOXA簇中的四个SNP（rs6668、rs 2428431、rs3801776和rs3779456）在发现样品中表现出改变的传递，但只有位于HOXA基础启动子区的rs3801776在发现和验证样品中表现出改变的传递（p=0.004和p=0.028）。有趣的是，HOXA 9在发育过程中在肌肉中表达。IGFBP 3中的SNP rs 13223993在发现样本中也显示出改变的传递（p=0.003）。在HOXA、HOXD和IGFBP 3的变异体之间以及与先前在神经细胞介导的凋亡基因中相关的SNP之间鉴定了基因-基因相互作用。在CASP 3 SNPS与HOXA、HOXD和IGFBP 3中的变体之间发现了最显著的相互作用。这些结果表明，马蹄内翻足的生物学模型中，HOX和凋亡基因的扰动一起影响肌肉和肢体发育，这可能会导致肢体旋转到足底等级位置的下游失败。
Clubfoot is a common birth defect that affects 135,000 newborns each year worldwide. It is characterized by equinus deformity of one or both feet and hypoplastic calf muscles. Despite numerous study approaches, the cause(s) remains poorly understood although a multifactorial etiology is generally accepted. We considered the HOXA and HOXD gene clusters and insulin-like growth factor binding protein 3 (IGFBP3) as candidate genes because of their important roles in limb and muscle morphogenesis. Twenty SNPs from the HOXA and HOXD gene clusters and 12 SNPs in IGFBP3 were genotyped in a sample composed of nonHispanic white and Hispanic multiplex and simplex families (discovery samples) and a second sample of nonHispanic white simplex trios (validation sample). Four SNPs (rs6668, rs2428431, rs3801776 and rs3779456) in the HOXA cluster demonstrated altered transmission in the discovery sample, but only rs3801776, located in the HOXA basal promoter region, showed altered transmission in both the discovery and validation samples (p=0.004 and p=0.028). Interestingly, HOXA9 is expressed in muscle during development. A SNP in IGFBP3, rs13223993, also showed altered transmission (p=0.003) in the discovery sample. Gene-gene interactions were identified between variants in HOXA, HOXD and IGFBP3 and with previously associated SNPs in mitochondrial-mediated apoptotic genes. The most significant interactions were found between CASP3 SNPS and variants in HOXA, HOXD and IGFBP3. These results suggest a biologic model for clubfoot in which perturbation of HOX and apoptotic genes together affect muscle and limb development, which may cause the downstream failure of limb rotation into a plantar grade position.
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TransFac及其模块移植：真核生物中的转录基因调节。
影响因子：
14.9
作者：
Matys V;Kel-Margoulis OV;Fricke E;Liebich I;Land S;Barre-Dirrie A;Reuter I;Chekmenev D;Krull M;Hornischer K;Voss N;Stegmaier P;Lewicki-Potapov B;Saxel H;Kel AE;Wingender E
通讯作者：
Wingender E
影响因子：
30.8
作者：
Abecasis, GR;Cherny, SS;Cardon, LR
通讯作者：
Cardon, LR
影响因子：
4.2
作者：
Ester, Audrey R.;Yerman, Gayle;Hecht, Jacqueline T.
通讯作者：
Hecht, Jacqueline T.
影响因子：
2.8
作者：
Dobbs, MB;Gurnett, CA;Bowcock, AM
通讯作者：
Bowcock, AM
影响因子：
4.2
作者：
Gurnett, Christina A.;Keppel, Cassie;Dobbs, Matthew B.
通讯作者：
Dobbs, Matthew B.